Sin Lee, a pathologist and scientist, believes the deck is stacked in the quest to air new ideas on Lyme disease.
Too many science journals telling him to take his research elsewhere. Too many deftly worded rejections. Too little inclination to engage in a fair fight over the facts and fiction of Lyme disease.
Dr. Lee's experience is shared by many researchers I have interviewed, in the U.S. and Europe, in five years of writing about a disease on which scientific debate is limited and tightly controlled. Some 380,000 Americans were infected with the tick-borne spirochete in 2015, leaving 20,000, by conservative estimates, with unresolved joint pain, cognitive lapses, fatigue and other problems. Another 232,000 are estimated to be infected annually in Western Europe. Many suffer because of a poor test and delayed diagnoses, issues that have been largely dismissed in mainstream journals.
Lee decided to take on some of the biggest names in Lyme disease, after their Dec. 15 publication of an article, in Nature Reviews Disease Primers, that repeated the doctrines that have ruled Lyme disease care for nearly a generation. But his effort to rebut the article, centering on his call for better early diagnosis, was quickly squelched.
'’Within days to weeks, [Lyme disease spirochetes] disseminate to other regions of the body or to other organs, the central nervous system, heart or joints.” — Steere article, which endorses waiting for a positive test to treat
"The point raised about requiring newer, better tests for diagnosis is undeniable, and the authors do discuss that," Primers' chief editor Mina Razzak wrote in a Dec. 20 email to Lee. "While I agree open dialogue and discussion is needed, this journal is not the best place for that...I am afraid we will not pursue publication of your letter." Yes we agree there are problems, the editor was saying. Sorry, we won't let you air them.
Lee, director of Milford Molecular Diagnostics, Milford, Connecticut, had other ideas, however. He posted his challenge on PubMed Commons, an open-access alternative that allows comment by published scientists, where it appeared below the article abstract.
Come back in a few weeks
The 850-word comment argues that Lyme infections have been allowed, even encouraged, to fester. How? Under long-established guidance, repeated in the article, that physicians wait for a positive test before treating patients without the Lyme rash. Lacking a good early test, doctors thus tell non-rash patients who have wrongly tested negative -- as 50 to 80 percent of early cases do, the paper admits -- to return in awhile, giving the insidious Lyme pathogen time to grow. By then, in what is called the convalescent phase, many patients feel better and do not return, only to be sickened later.
"The authors seem to advise the medical practitioners to not treat Lyme disease patients until the proliferating spirochetes in the host have elicited certain immune responses which can be confirmed by serologic tests," wrote Lee, capturing the inexplicable logic of a flawed test. "Such practice should not be accepted or continued for obvious reasons."
The article's lead author was Allen Steere, who first investigated the disease when it emerged in Connecticut in the 1970s. Others included Gary Wormser, lead author of controversial Lyme treatment guidelines; Frank Strle, another guidelines author, and Paul Mead, an epidemiologist who has specialized in vector-borne diseases at the U.S. Centers for Disease Control and Prevention.
On behalf of the CDC, Mead disputed Lee's critique. "CDC encourages prompt treatment of early Lyme disease. The suggestion that CDC is advising medical practitioners to withhold treatment until after the organism has disseminated is [his emphasis] incorrect," he wrote in an emailed statement. "The recommendations for serologic testing are for patients who already have signs and symptoms suggestive of disseminated infection."
Lyme disease can be diagnosed early, the CDC website states, ‘in patients who present with [a Lyme] rash.’ It does not say anything about people with symptoms but not the rash.
But patients have symptoms before the disease has disseminated, according to the CDC itself. Its website lists three symptoms of "localized" -- or not disseminated -- infection: the rash, flu-like symptoms and swollen lymph nodes. However, the agency includes just one symptom to support diagnosis: "During the localized (early) stage of illness, Lyme disease may be diagnosed clinically in patients who present with [a Lyme] rash." Not the flu, not abnormal lymph nodes.
CDC's fine line
While the CDC's website is carefully worded, the paper that Mead signed onto is crystal clear: "Demonstration of borrelial infection by laboratory testing is required for reliable diagnosis of Lyme borreliosis, with the exception of erythema migrans," the name for the reddish Lyme rash.
In one venue, namely the article on which he is a co-author, Mead is unequivocal that only tests can diagnose early non-rash infection. In the other, he and the CDC walk a fine line, approving diagnosis for those with the rash, but silent on the rest.
I asked Mead whether the CDC agreed with the article's contention that a positive test is "required" without the rash, which, a CDC web page says, appears in 60 to 80 percent of cases. He noted that the article refers to "reliably" diagnosing, as opposed to treating, early disease, a distinction perhaps without a difference. He nonetheless left room for treatment based on symptoms.
With regard to empiric treatment of possible early Lyme disease," he wrote, "clinicians should consider the patient's signs and symptoms, the many other diseases that may produce similar symptoms (including other tickborne and non-tickborne infections), and the risks and benefits of presumptive antibiotic treatment."
'If you try to publish a little bit different from the guidelines, it's anti-science.' -- Christian Perronne, French physician
While espousing a wait-and-see position, the Steere article makes clear the risks of on-the-loose Borrelia burgdorferi, the pathogen that causes Lyme disease: "Within days to weeks, the strains of B. burgdorferi in the United States commonly disseminate from the site of the tick bite to other regions of the body. B. burgdorferi can spread to other skin sites...or to other organs, particularly to the peripheral and/or central nervous system (CNS), heart or joints."
Told not to diagnose early on without a rash, doctors -- and patients -- therefore must wait those "days to weeks" for the spirochete to move, antibodies to be produced, and a test to turn positive. There seems little other choice under both the Infectious Diseases Society of America's guidelines and the Steere article. (Steere did not respond to several requests for comment.)
In his commentary on the article, Lee wrote that Steere, Mead and colleagues had "glossed over" one of the most urgent issues in Lyme disease care: the huge flaws in the test regime that by definition misses early cases. Under it, patients must test positive twice -- the so-called two-tier test -- with many patients failing to clear the first in order to get to the second because they have not produced the requisite antibodies. Lee advocates use of DNA sequencing to diagnose the disease and has published scientific articles supporting it, finding a home in international journals after rejections by U.S.-affiliated journals.
When I told him of Mead's response, Lee said CDC's claim of encouraging early treatment "is merely a lip service." He noted that Mead confirmed the tests are advised for people with disseminated infection "but has offered no alternative testing...or taken any actions to encourage development of such testing."
Indeed, the two-tier test has been in use since the mid-1990s despite widespread acknowledgement that it is unreliable early in the disease; later on, its performance is better, with significant exceptions based mostly on how it has been validated. Reliance on a poor test may in part explain why many people remain sick after delayed or failed diagnoses. A Lymedisease.org survey found that three times the share of patients diagnosed early reported getting well compared to those whose diagnoses were delayed.
Tests: 'Stop-gap measure'
In researching my book on the global spread of tick-borne disease, I spoke about the testing regimen with Raymond Dattwyler, an author of the Lyme protocols who was on the 1994 CDC panel that wrote the test guidelines. He was frank about its failures.
"They were a stop-gap measure," he told me. "Twenty years ago I would've said they're fine. Now I say, 'oh shit, we were wrong.' It doesn't look as good as we thought it was." Like Lee, Dattwyler is working on an improved test that he hopes will come into use in the next 18 months. Dattwyler also spoke publicly about the test's flaws at a conference in Ottawa last May.
Steere's article repeats 'myths about Lyme disease diagnosis (and) the dreadful state of 30-year-old' test. -- Raphael Stricker, Lyme physician and author
Other commenters also raised questions about the Steere article. Marcia Herman-Giddens, an adjunct professor at Gillings School of Global Public Health at the University of North Carolina, disputed the article's premise that about 80 percent of Lyme patients manifest the signature rash that is so integral to early diagnosis. "There has never been a well-designed study to examine this issue," she wrote. "(T)he true incidence is likely lower," she added.
Raphael Stricker, a physician who has written extensively on Lyme disease, commented, "The primer propagates one of the biggest myths about Lyme disease diagnosis instead of acknowledging the dreadful state of 30-year-old Lyme serology and the need for better testing."
False positives: 'Red herring'
The insistence on positive tests in patients without the Lyme rash grows out fear of falsely diagnosing and treating people who do not have the disease, since Lyme symptoms often overlap with other maladies. Over-diagnosis has been a theme in Lyme literature starting with a Steere study in 1993 and repeated in about 30 other studies since. But the fear of unnecessarily treating some patients, with antibiotics that are widely considered safe, comes at the expense of not treating others whose illness may therefore become resistant to cure.
Benjamin Luft, a physician who wrote the original Lyme disease guidelines in 2000 but who now sees them as flawed on the issue of whether Lyme disease can persist, called the false positive issue "a red herring."
"I think there's a great deal of benefit for early treatment than delay," he said in an interview. "It does become progressively more difficult [to treat] as time goes on."
Like Lee, other researchers have had difficulty getting published, which I will write about in my book. In being rebuffed for grants or publications, they have been told, in one case, Lyme "is a middle-class disease;" in another, "Lyme isn't that much of a problem, and there's a vaccine anyway," which there wasn't then and isn't now. Lee was once told a paper "did not achieve a high enough priority score," a reflection of how the biggest vector-borne epidemic in the U.S. has been packaged and viewed. It is a disease without urgency because, the dogma goes, tests and treatments work.
"I've tried to publish in many journals," Christian Perronne, a physician on the infectious diseases faculty at the University of Versailles-St Quentin, France, told a conference in Norway in 2014 and repeated those assertions when I spoke with him. "If you try to publish a little bit different from the guidelines, it's anti-science."
'Your paper did not achieve a high enough priority score.' -- Editor's rejection of Lyme disease article
Nonetheless, there is a great deal of science to suggest the standard Lyme disease test does not work well, including two large studies published in 2016. A review in BMC Infectious Diseases of 78 studies of the standard diagnostic test in Europe concluded: "(T)he data in this review do not provide sufficient evidence to make inferences about the value of the tests for clinical practice." It also found "a high risk of bias" in every study - they excluded all "difficult to diagnose" patients - calling into question even their feeble performance findings.
A separate analysis of 50 studies, published in the International Journal of General Medicine, found that tests used by laboratories to diagnose Lyme disease got it right on average 59.5 percent of the time for all stages of the disease.
These studies beg the question of why the test has endured since 1994, a relic of a CDC conference in Dearborn, Michigan. Moreover, why do papers like Steere's continue to insist that only a flawed test can validate Lyme disease?
Lee, meantime, believes DNA sequencing protocols will prove definitive and notes it is used elsewhere, in particular to identify the Ebola virus.
"Whether I am right or not is immaterial," he said. "The important thing is that we should cut out the tribalism in dealing with the diagnosis of Lyme disease, and have a roundtable discussion."
Mary Beth Pfeiffer's book on the global spread of Lyme and tick-borne diseases is to be published in 2018 by Island Press. Follow her on Twitter: @marybethpf